Stereoisomers propofol therapeutic compounds

ABSTRACT

A (+)-stereoisomer of formula (I): wherein X is H or F; or a pharmaceutically acceptable salt or prodrug thereof, useful as an anesthetic.

The present application is a Continuation of application Ser. No.12/596,800, filed May 28, 2010, which is a 371 National PhaseApplication of PCT/US2008/063082 filed on May 8, 2008 which claims thebenefit of U.S. provisional patent application No. 60/928,327 filed onMay 9, 2007; U.S. provisional patent application No. 60/928,429 filed onMay 9, 2007 and U.S. provisional patent application No. 60/928,296 filedon May 9, 2007, in which the enclosures are incorporated by reference intheir entireties.

BACKGROUND OF THE INVENTION

Propofol (2,6-diisopropylphenol) is an intravenous sedative/hypnoticagent used extensively for induction and maintenance of generalanesthesia, sedation of critically ill patients and procedural sedation(e.g., endoscopy). See Langly, M. S. and Heel, R. C. Drugs, 1988, 35,334-372. Propofol is only sparingly soluble in water and is currentlymarketed in a 10% soybean oil based lipid emulsion similar toformulations used for parenteral nutrition.

Propofol is a GABA_(A) agonist that activates multiple GABA_(A) receptorsubtypes, which are ion channels that transport chlorine anions acrosscell membranes, in the central nervous system. Although propofol isachiral, racemic mixtures of a number of dialkyl phenols are knownagonists of the GABA_(A) receptor (James et al., J. Med. Chem. 23, 1350,1980; Krasowski et al., J. Pharmacol. & Exp. Therapeutics 297, 338,2001). James et al., report finding propofol to be superior in itsoverall profile to other analogues evaluated.

Propofol is preferred by many clinicians due to its excellentpharmacokinetic, pharmacodynamic, emergence and recovery profiles.However, undesired side-effects (e.g., respiratory depression, ICUsyndrome, injection pain and hemodynamic effects) produced at or nearthe therapeutic dose greatly limit its utility in multiple clinicalsettings. Of particular concern are the hemodynamic effects.Administration of propofol, particularly in bolus form, often producesdecreases in blood pressure without a compensatory increase in heartrate. A variety of clinical conditions are incompatible with the use ofpropofol because of undesired and potentially harmful hemodynamicconsequences. Examples of such conditions include cardiovascular diseasesuch as coronary artery disease, cardiomyopathy, ischemic heart disease,valvular heart disease, and congenital heart disease. Chronichypertension, cerebrovascular disease, brain injury, and advanced agecan make the use of propofol difficult or problematic because of itshemodynamic properties. Patients with acute blood loss, dehydration, orsevere infection including those with hemorrhagic shock, hypovolemicshock, or septic shock may be exposed to excessive hazard were propofolemployed. The hemodynamic properties of propofol may limit its use inpatients receiving other medications or treatments such as spinalanesthesia, epidural anesthesia, or vasoactive medications.

SUMMARY OF THE INVENTION

The invention provides therapeutic compounds that demonstrate similar orimproved pharmacological activity compared to propofol along with animproved hemodynamic profile.

Accordingly, in one embodiment the invention provides a (−)-stereoisomerof formula (I):

wherein X is H or F, or a salt or prodrug thereof.

The invention also provides a pharmaceutical composition comprising a(−)-stereoisomer of formula (I) or a pharmaceutically acceptable salt orprodrug thereof and a pharmaceutically acceptable carrier.

The invention also provides a method to treat nausea, vomiting,migraine, neurodegenerative conditions of the nervous system (e.g.,Friedrich's disease, Parkinson's disease, Alzheimer's disease,Huntington's disease, amyotrophic lateral sclerosis (ALS), multiplesclerosis (MS), Pick disease, etc.), trauma to the central nervoussystem (e.g., skull fracture and its resulting edema, concussion,contusion, brain hemorrhages, shearing lesions, subdural and epiduralhematoma, and spinal cord injury (e.g., mechanical injury due tocompression or flexion of the spinal cord)), seizures (e.g., epilepticseizures) or a free radical associated disease (e.g., ischemicreperfusion injury, inflammatory diseases, systemic lupus erythematosis,myocardial infarction, stroke, traumatic hemorrhage, cataract formation,uveitis, emphysema, gastric ulcers, neoplasia, radiation sickness, etc.)in an animal comprising administering an effective amount of a(−)-stereoisomer of formula (I) or a pharmaceutically acceptable salt orprodrug thereof to the animal.

The invention also provides a method for inducing or maintaining generalanesthesia in an animal comprising administering an effective amount ofa (−)-stereoisomer of formula (I) or a pharmaceutically acceptable saltor prodrug thereof to the animal.

The invention also provides a method for promoting sedation in an animalcomprising administering an effective amount of a (−)-stereoisomer offormula (I) or a pharmaceutically acceptable salt or prodrug thereof tothe animal.

The invention also provides a method for treating a migraine in ananimal comprising administering an effective amount of a(−)-stereoisomer of formula (I) or a pharmaceutically acceptable salt orprodrug thereof to the animal.

The invention also provides a method for treating insomnia in an animalcomprising administering an effective amount of a (−)-stereoisomer offormula (I) or a pharmaceutically acceptable salt or prodrug thereof tothe animal.

The invention also provides a method for promoting an anxiolytic effectin an animal comprising administering an effective amount of a(−)-stereoisomer of formula (I) or a pharmaceutically acceptable salt orprodrug thereof to the animal.

The invention also provides a method for treating addiction withdrawalin an animal comprising administering an effective amount of a(−)-stereoisomer of formula (I) or a pharmaceutically acceptable salt orprodrug thereof to the animal.

The invention also provides a method for promoting an antiemetic effectin an animal comprising administering an effective amount of a(−)-stereoisomer of formula (I) or a pharmaceutically acceptable salt orprodrug thereof to the animal.

The invention also provides a method for agonizing a GABA receptorcomprising contacting the receptor (in vitro or in vivo) with aneffective amount of a (−)-stereoisomer of formula (I) or apharmaceutically acceptable salt thereof.

The invention also provides a method for agonizing a GABA receptor in ananimal comprising administering an effective amount of a(−)-stereoisomer of formula (I) or a pharmaceutically acceptable salt orprodrug thereof to the animal.

The invention also provides a (−)-stereoisomer of formula (I) or apharmaceutically acceptable salt or prodrug thereof for use in medicaltherapy.

The invention also provides the use of a (−)-stereoisomer of formula (I)or a pharmaceutically acceptable salt or prodrug thereof to prepare amedicament for treating nausea, vomiting, migraine, neurodegenerativeconditions of the nervous system (e.g., Friedrich's disease, Parkinson'sdisease, Alzheimer's disease, Huntington's disease, amyotrophic lateralsclerosis (ALS), multiple sclerosis (MS), Pick disease, etc.), trauma tothe central nervous system (e.g., skull fracture and its resultingedema, concussion, contusion, brain hemorrhages, shearing lesions,subdural and epidural hematoma, and spinal cord injury (e.g., mechanicalinjury due to compression or flexion of the spinal cord)), seizures(e.g., epileptic seizures) or a free radical associated disease (e.g.,ischemic reperfusion injury, inflammatory diseases, systemic lupuserythematosis, myocardial infarction, stroke, traumatic hemorrhage,cataract formation, uveitis, emphysema, gastric ulcers, neoplasia,radiation sickness, etc.) in an animal.

The invention also provides the use of a (−)-stereoisomer of formula (I)or a pharmaceutically acceptable salt or prodrug thereof to prepare amedicament for inducing or maintaining general anesthesia in an animal.

The invention also provides the use of a (−)-stereoisomer of formula (I)or a pharmaceutically acceptable salt or prodrug thereof to prepare amedicament for promoting sedation in an animal.

The invention also provides the use of a (−)-stereoisomer of formula (I)or a pharmaceutically acceptable salt or prodrug thereof to prepare amedicament for treating a migraine in an animal.

The invention also provides the use of a (−)-stereoisomer of formula (I)or a pharmaceutically acceptable salt or prodrug thereof to prepare amedicament for treating insomnia in an animal.

The invention also provides the use of a (−)-stereoisomer of formula (I)or a pharmaceutically acceptable salt or prodrug thereof to prepare amedicament for promoting an anxiolytic effect in an animal.

The invention also provides the use of a (−)-stereoisomer of formula (I)or a pharmaceutically acceptable salt or prodrug thereof to prepare amedicament for treating addiction withdrawal in an animal.

The invention also provides the use of a (−)-stereoisomer of formula (I)or a pharmaceutically acceptable salt or prodrug thereof to prepare amedicament for promoting an antiemetic effect in an animal.

The invention also provides the use of a (−)-stereoisomer of formula (I)or a pharmaceutically acceptable salt or prodrug thereof to prepare amedicament for agonizing a GABA receptor in an animal.

The invention also provides synthetic processes and intermediatesdisclosed herein that are useful for preparing a (−)-stereoisomer offormula (I) or a salt or prodrug thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the effect on mean arterial blood pressure (mm Hg) in pigsfollowing IV infusion of the (−) stereoisomer of formula (I) in which Xis H in comparison with propofol.

FIG. 2 shows the effect on heart rate (beats per minute) in pigsfollowing IV infusion of the (−) stereoisomer of formula (I) in which Xis H in comparison with propofol.

FIG. 3 shows the effect on cardiac output (liters per minute, or L/min)in pigs following IV infusion of the (−) stereoisomer of formula (I) inwhich X is H in comparison with propofol.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a (−) stereoisomer of formula (I), or asalt or prodrug thereof as defined hereinabove.

The absolute configuration of such a stereoisomer has been determined tobe (R,R).

In one embodiment, X is H. When X is H, the stereoisomer may also bereferred to by the name (R,R)-2,6-di-sec-butylphenol.

Compared with propofol, (R,R)-2,6-di-sec-butylphenol has been found todemonstrate a surprisingly improved overall profile of activity as ananesthetic. More particularly, the compound has been found to produce amore potent effect on anesthetic activity, to exhibit a highertherapeutic index and to retain a comparable pharmacokinetic profile,e.g., exhibit a similar clearance rate. The compound also can produce aless potent effect on mean arterial pressure, heart rate and/or cardiacoutput. Furthermore, it is believed that clinical trials willdemonstrate that the compound causes less pain on injection thanpropofol. Injection pain associated with propofol has been correlated tothe concentration of propofol in the aqueous phase of its lipid emulsionvehicle. When formulated in identical lipid emulsions, the aqueous phaseconcentration of (R,R)-2,6-di-sec-butylphenol has been found to besignificantly reduced (by more than 90%) compared to propofol.

The other two isomers of 2,6-di-sec-butylphenol, the (S,S) or (+) and(meso) stereoisomers have also been found, unexpectedly, to demonstrateimproved hemodynamic profiles along with similar or improvedpharmacological activities, compared to propofol. However, the improvedoverall profile of activity as an anesthetic of(R,R)-2,6-di-sec-butylphenol has been found to be unique to this isomerof this dialkylphenol.

Accordingly, compounds according to the invention are particularlyuseful for inducing or maintaining general anesthesia or promotingsedation in a patient. They are particularly useful for anesthetizingpatients having an elevated susceptibility to hemodynamic effects. Suchpatients include patients suffering from cardiovascular disease such ascoronary artery disease, cardiomyopathy, ischemic heart disease,valvular heart disease, and congenital heart disease; patients sufferingfrom chronic hypertension, cerebrovascular disease, or brain injury;patients of an advanced age (for example over 50, 60, 70 or 80 yearsold); patients with acute blood loss, dehydration, or severe infectionincluding those with hemorrhagic shock, hypovolemic shock, or septicshock; and patients receiving spinal anesthesia, epidural anesthesia, orvasoactive medications; see e.g., Reich D L et al, 2005. Anesth Analg101, 622. For example, the patient may be one for whom the AmericanSociety of Anesthesiologists (ASA) physical status is at least 3. Thepresent invention also contemplates administering compounds according tothe invention to patients that have not been pre-medicated for pain oninjection.

As used herein, the term “Pharmaceutically acceptable carrier” includesdiluents, adjuvants, excipients or vehicles.

The term “Animal” includes mammals such as, for example, humans,companion animals, zoo animals and livestock.

The term “Treating” a disease or disorder includes 1) ameliorating thedisease or disorder (i.e., arresting or reducing the development of thedisease or disorder or at least one of the clinical symptoms thereof),2) ameliorating at least one physical parameter, which may not bediscernible by the patient, 3) inhibiting the disease or disorder whichcan be either physically, (e.g., stabilization of a discerniblesymptom), physiologically, (e.g., stabilization of a physical parameter)or both, or 4) delaying the onset of the disease or disorder.

Stereoisomeric purity of compounds and prodrugs described herein may beestablished by conventional analytical methods well known to those ofskill in the art. For example, use of chiral NMR shift reagents, gaschromatographic analysis using chiral columns, high pressure liquidchromatographic analysis using chiral columns, polarimetry, isotopicdilution, calorimetry, enzymatic methods, capillary electrophoresis onchiral gels, formation of diastereomeric derivatives through reactionwith chiral reagents and conventional analysis via establishedanalytical methods may be used to establish the stereochemical purity ofa specific stereoisomer. Alternatively, synthesis using startingmaterials of known stereochemical enrichment may be used to establishthe stereochemical purity of the compounds described herein. Otheranalytical methods for demonstrating stereochemical homogeneity areknown in the field.

The present invention provides a stereoisomer of formula (I) or a saltor prodrug thereof in a non-racemic (i.e., an enantiomerically enriched)form at the centers marked by “*” in formula (I). Thus the inventionincludes a stereoisomer of formula (I) in an enriched mixture thatcontains no more than 45% of other enantiomers or diastereomers of thatcompound of formula (I) that is shown or its salt or prodrug. The(−)-enantiomer isolated in Example 1 below is a specific stereoisomer ofthe invention. In some embodiments of the invention, an enriched mixturecontains no more than about 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 4%,3%, 2%, or 1% of other enantiomers or diastereomers of a compound offormula (I) or its salt or prodrug. In another embodiment of theinvention an enriched mixture contains less than about 1% of otherenantiomers or diastereomers of a compound of formula (I) or its salt orprodrug.

Methods for Preparing a Compound of Formula (I)

Generally, compounds of formula (I) may be prepared by at least threedifferent approaches. In one approach, a racemic and/or diastereomericmixture is prepared using conventional methods of organic synthesis orpurchased from commercial sources and the mixture resolved using methodsknown to those of skill in the art such as, for example, fractionalcrystallization, separation on chiral columns (See Example 1 below),formation of derivatives and separation or kinetic resolution thereof,etc. to provide substantially pure stereoisomers of formula (I) orstereoisomerically enriched mixtures of compounds of formula (I).Alternatively, asymmetric synthesis may be used to prepare compounds offormula (I). Known chiral precursors can be used to preparesubstantially pure stereoisomers of formula (I) or stereoisomericallyenriched mixtures of compounds of formula (I) using known methods. Othermethods include preparation of chiral intermediates using, for example,enantioselective hydrogenation, enantioselective reduction,enantioselective carbon-carbon bond formation, enzymatic cleavage ofracemic acetates, etc., followed by conversion to a compound of formula(I) using conventional methods of organic synthesis.

In one method, a stereoisomer of formula (I) can be prepared using achiral isocyanate to form a mixture of carbamate diastereomers that canbe separated to yield the desired diastereomer of formula (I) afterhydrolysis of the carbamate residue.

According to another aspect, therefore, the present invention provides aprocess for preparing a (−) stereoisomer of formula (I) or a salt orprodrug thereof, which comprises hydrolysing a carbamic acid(−)-2,6-di-sec-butylphenyl ester diastereoisomer of formula

in which R¹ represents a chiral amino group, followed if required byforming the free phenol or a salt (such as a pharmaceutically acceptablesalt) or pro-drug thereof.

The hydrolysis may be effected by reacting the carbamate with a base,for example an alkali metal hydroxide, such as potassium or sodiumhydroxide, which affords a salt of the (−) stereoisomer of formula (I),such as an alkali metal salt. The free phenol may be obtained bytreating this salt with an acid, such as hydrochloric acid. The chiralamino group may be, for example, a chiral 1-arylethylamino group, forexample an (R)-1-arylethylamino group such as (R)-1-phenylethylamino.

The carbamate starting material may be prepared by reacting a racemicmixture of the corresponding 2,6-di-sec-butylphenol with a chiralisocyanate to afford a mixture of diastereoisomers comprising thecarbamic acid (−)-2,6-di-sec-butylphenyl ester diastereoisomer; andseparating the corresponding carbamic acid (−)-2,6-di-sec-butylphenylester diastereoisomer of formula (II).

The chiral isocyanate may be, for example, a chiral1-arylethylisocyanate, for example an (R)-1-arylethylisocyanate such as(R)-(+)-1-phenylethylisocyanate. The resultant product is a mixture ofthe corresponding 1-arylethylcarbamic acid 2-sec-butyl-6-isopropylphenylester diastereoisomers. The desired diastereoisomer can be separated bychromatography using, for example, silica as the stationary phase, or bycrystallization.

It has been found, surprisingly, that the use ofR-(+)-1-phenylethylisocyanate in the above-described method provides anexceptionally good separation of the stereoisomers of2,6-di-sec-butylphenol, compared with the use of other chiral acylatingor sulfonating reagents, such as chiral carboxylic acids or chiralsulfonic acids.

Processes for preparing a stereoisomer of formula (I) or a salt thereofare provided as further embodiments of the invention.

Salts

In cases where compounds are sufficiently acidic, a salt of a compoundof formula (I) can be useful as an intermediate for isolating orpurifying a compound of formula (I) or an enriched mixture thereof.Additionally, administration of a compound of formula (I) as apharmaceutically acceptable salt may be appropriate. Examples ofpharmaceutically acceptable salts include salts that are obtained usingstandard procedures well known in the art, for example by reacting asufficiently acidic compound of formula (I) with a suitable baseaffording a physiologically acceptable cation. For example, alkali metal(for example, sodium, potassium or lithium) or alkaline earth metal (forexample calcium) salts can be made.

Pharmaceutical Compositions

The pharmaceutical compositions disclosed herein comprise a compound offormula (I) disclosed herein with a suitable amount of apharmaceutically acceptable carrier, so as to provide a form for properadministration to a patient. The compounds of formula (I) may beformulated as pharmaceutical compositions and administered to a patient,in a variety of forms adapted to the chosen route of administration,e.g., orally, parenterally, intravenously, intramuscularly, topically orsubcutaneously.

Thus, the compounds of formula (I) can be systemically administered, incombination with pharmaceutically acceptable carriers such as inertdiluents or edible carriers. Such compositions and preparations maycontain at least 0.1% of active compound. The percentage of thecompositions and preparations can, of course, be varied and canconveniently be between about 0.1% to about 60% of the weight of a givenunit dosage form. The amount of active compound in such therapeuticallyuseful compositions is such that an effective dosage level is obtained.

The compounds of formula (I) described herein are typically formulatedas pharmaceutical compositions suitable for intravenous administration.The compounds of formula (I) may be relatively insoluble in water. Thus,for intravenous administration, the compounds of formula (I) aretypically formulated in aqueous media using one or more water-immisciblesolvents and one or more emulsifiers or surfactants. Individualformulations can include one or more additional components such asstabilizers, tonicity modifiers, bases or acids to adjust pH andsolubilizers. The formulations may also optionally contain apreservative, such as, for example, ethylenediaminetetraacetic acid(EDTA) or sodium metabisulfite. Useful oil-in-water emulsions thatcontain a preservative such as EDTA that may be used in conjunction withcompounds described herein are described in U.S. Pat. Nos. 5,908,869,5,714,520, 5,731,356 and 5,731,355.

A wide range of water-immiscible solvents can be used in thepharmaceutical compositions described herein. The water-immisciblesolvent can be a vegetable oil, such as, for example, soybean,safflower, cottonseed, corn, sunflower, arachis, castor or olive oil.Alternatively, the water-immiscible solvent may be an ester of a mediumor long-chain fatty acid, such as, for example, a mono-, di-, ortriglyceride, an ester of a combination of a medium and long-chain fattyacid or a chemically modified or manufactured material such as ethyloleate, isopropyl myristate, isopropyl palmirate, a glycerol ester,polyoxyl or hydrogenated castor oil. The water-immiscible solvent canalso be a marine oil, such as, for example cod liver or anotherfish-derived oil. Other suitable solvents include fractionated oils,such as, for example, fractionated coconut oil or modified soy bean oil.The water-immiscible solvent may include “structured lipids.” (see,e.g., Lipid Biotechnology, T. M. Kuo and H. W. Gardner (eds.), MarcelDekker, Inc. New York, N.Y.). Many structured lipids are available fromcommercial suppliers such as Danisco A/S, Copenhagen Denmark and S&JLipids, Ostrander, Ohio.

The pharmaceutical compositions described herein can also contain anemulsifier. Suitable emulsifiers include synthetic non-ionicemulsifiers, such as, for example, ethoxylated ethers, ethoxylatedesters, polyoxypropylene-polyoxyethylene block co-polymers andphospholipids. Naturally-occurring phospholipids, such as egg or soyaphospholipids, and modified or artificially manipulated phospholipids ormixtures thereof can also be used. In some embodiments, emulsifiers areegg phospholipids and soya phospholipids. Egg yolk phospholipids includephosphatidylcholine, lecithin and phosphatidylethanolamine.

The pharmaceutical formulations described herein can comprise a lipidemulsion comprising from about 0.1% to about 5% (w/w) of a formula (I)compound, from about 5 to about 25% (w/w) water immiscible solvent andfrom about 40% to about 90% (w/w) water. A preferred formulationcomprises from about 0.5% to about 2% (w/w) of a formula (I) compound.In one embodiment, a pharmaceutical formulation comprises from about0.5% to about 5% (w/w) of a formula (I) compound and from about 0% toabout 50% (w/w) of a water immiscible solvent.

The pharmaceutical formulations described herein may also includestabilizing agents. Anionic stabilizers include, for example,phosphatidylethanolamines, conjugated with polyethylene glycol, (PEG-PE)and phosphatidylglycerols, a specific example of which isdimyristolphosphatidylgylcerol (DMPG). Additional stabilizers include,but are not limited to, oleic acid and its sodium salt, cholic acid anddeoxycholic acid and respective salts thereof, cationic lipids such asstearylamine and oleylamine, and3|3-[N—(N′,N′-dimethylaminoethane)carbamoyl]cholesterol (DC-Chol).

The pharmaceutical compositions described herein can be made isotonicwith blood by the incorporation of a suitable tonicity modifier.Glycerol is most frequently used as a tonicity modifier. Alternativetonicity modifying agents include xylitol, mannitol and sorbitol. Thepharmaceutical compositions are typically formulated to be atphysiologically neutral pH, typically in the range 6.0-8.5. The pH canbe adjusted by the addition of base, for example, NaOH or NaHCO₃, or insome cases acid, such as HCl.

The compounds of formula (I) can be formulated with pharmaceuticallysafe oil-water emulsions comprising a vegetable oil, a phosphatideemulsifier, typically egg lecithin or soybean lecithin, and a tonicitymodifier such as, for example. Liposyn® II and Liposyn® III (AbbottLaboratories, North Chicago. IL) and Intralipid® (Fresenius Kabi AB,Uppsala, Sweden) or other similar oil-water emulsions.

Compounds of formula (I) can also be formulated in a triglyceridecomprising esters of at least one medium chain length (C₆-C₁₂) fattyacid. In some embodiments, the triglyceride is an ester of a C₈-C₁₀fatty acid. Triglycerides suitable for formulating compounds of formula(I) include, but are not limited to, Miglyol® (Condea Chemie GmbH(Witten, Germany). For example, Miglyol® 810 or 812 (caprylic(C₁₀)/capric (C₈) glyceride) is useful for formulation of compounds offormula (I).

Additionally, compounds of formula (I) described herein can beformulated analogously to pharmaceutical compositions of propofol asdescribed, for example, in U.S. Pat. Nos. 4,056,635, 4,452,817 and4,798,846.

Still other suitable formulations for use in the present invention canbe found, for example in Remington's Pharmaceutical Sciences,Philadelphia, Pa., 19th ed. (1995).

Therapeutic/Prophylactic Administration And Doses

A compound of formula (I) and/or pharmaceutical compositions thereof maybe administered alone or in combination with other pharmaceutical agentsincluding compounds disclosed herein and/or pharmaceutical compositionsthereof. The compounds disclosed herein may be administered or appliedper se or as pharmaceutical compositions. The specific pharmaceuticalcomposition depends on the desired mode of administration, as is wellknown to the skilled artisan.

Compounds disclosed herein and/or pharmaceutical compositions thereofmay be administered to a subject by intravenous bolus injection,continuous intravenous infusion, oral tablet, oral capsule, oralsolution, intramuscular injection, subcutaneous injection, transdermalabsorption, buccal absorption, intranasal absorption, inhalation,sublingually, intracerebrally, intravaginally, rectally, topically,particularly to the ears, nose, eyes, or skin or any other convenientmethod known to those of skill in the art. In some embodiments,compounds disclosed herein and/or pharmaceutical compositions thereofare delivered via sustained release dosage forms, including oralsustained release dosage forms. Administration can be systemic or local.Various delivery systems are known, (e.g., encapsulation in liposomes,microparticles, microcapsules, capsules, “patient controlled analgesia”drug delivery systems, etc.) that can be used to deliver compoundsdisclosed herein and/or pharmaceutical compositions thereof.

The amount of compounds disclosed herein and/or pharmaceuticalcompositions thereof that will be effective can be determined bystandard clinical techniques known in the art. The amount of compoundsdisclosed herein and/or pharmaceutical compositions thereof administeredwill, of course, be dependent on, among other factors, the subject beingtreated, the weight of the subject, the age of the subject, thecondition of the subject, the intended effect of the compounds, themanner of administration and the judgment of the prescribing physician.For example, the dosage level of a (R,R) or (−) stereoisomer of formula(I) for producing general anesthesia may be in the range of from about 1to about 10 mg/kg. Preferred induction doses range from about 1 to about2.5 mg/kg. Preferred maintenance doses range from about 1 to about 15mg/kg/hr. Preferred doses to produce a sedative effect range from about0.3 to about 6 mg/kg/hr.

Combination Therapy

In certain embodiments, compounds disclosed herein and/or pharmaceuticalcompositions thereof can be used in combination therapy with at leastone other therapeutic agent. The compounds disclosed herein and/orpharmaceutical compositions thereof and the therapeutic agent can actadditively or, more preferably, synergistically. In some embodiments,compounds disclosed herein and/or pharmaceutical compositions thereofare administered concurrently with the administration of anothertherapeutic agent such as, for example, other sedative hypnotic agents(e.g., etomidate, thiopental, midazolam, dexmedetomidine, ketamine),anesthetic agents (e.g., desflurane, sevoflurane, isoflurane, nitrousoxide), analgesics (e.g., an opioid such as remifentanil, morphine,meperidine, hydromorphone, methadone, fentanyl, sulfentanil, oralfentanil, or a non-opioid analgesic such as ketorolac, gapapentin,lidocaine, or ketamine), paralytic agents, such as rocuronium,cis-atracurium, vecuronium, or pancuronium bromide, anti-emetics (e.g.,ondansetron, dolasetron, droperidol), cardiovascular agents (e.g.,metoprolol, propranolol, esmolol, clonidine, phenylephrine, ephedrine,epinephrine, norepineprine, dopamine, diltiazem, atropine,glycopyrrolate, lisinopril, nitroglycerin, sodium nitroprusside,digoxin, milrinone), steroids (e.g. dexamethasone, hydrocortosone,methylprednisolone), anti-infective agents (e.g., cefazolin,vancomycin), diuretics (e.g., furosemide, hydrochlorothiazide,spironolactone), mood altering medications (e.g., fluoxetine,aripiprazole), or stimulants such as nicotine or cytisine.

For example, compounds disclosed herein and/or pharmaceuticalcompositions thereof may be administered together with other therapeuticagents. In other embodiments, compounds disclosed herein and/orpharmaceutical compositions thereof are administered prior or subsequentto administration of other therapeutic agents.

Prodrugs

The term “prodrug” as used herein refers to a compound that can bemetabolized or converted in vivo to provide a compound of formula (I).Typically, prodrugs include compounds that are prepared by modifying thephenol group in a compound of formula (I) to provide a correspondingcompound that can be metabolized or converted in vivo to provide thecorresponding compound of formula (I). Prodrugs of phenolic compounds aswell as methods for their preparation have been reported. For example,see U.S. Patent Application Publication Numbers 20070015716,20060287525, 20060205969, 20060041011, 20050239725, and 20050107385.

Other suitable prodrug groups are discussed in the following PublishedInternational Patent Applications and Published US Patent Applications:WO 2005023204; US 2005107385; US 2005004381; WO 2004092187; WO2004032971; US 2006100163; WO2006033911; WO 2004033424; US 2005267169;WO2003086413; US 2002370213; WO 2003057153; US 2001342755; US2002099013; WO 2002034237; US 2004127397; WO 2002013810; WO 2000048572;US 2006166903; WO 200008033; US 2001025035; WO 9958555; and US199875356; and in the other following publications: Krasowski, M. D.Current Opinion in Investigational Drugs (Thompson Scientific) (2005)6(1), 90-98; Fechner, J. et al., Anesthesiology, 2004. 101, 3, 626-639;Altomare C. et al., European Journal of Pharmaceutical Sciences; 2003,20, 1, 17-26; Sagara, Y. et al., Journal of Neurochemistry: 1999; 73, 6,2524-2530, and Trapani, G., et al., International Journal ofPharmaceuticals, 1998, 175, 2, 195-204.

As described hereinabove, the other two isomers of2,6-di-sec-butylphenol, the (S,S) or (+) and (meso) isomers of formula(I), have also been found to demonstrate an improved hemodynamic profilealong with a similar or improved pharmacological activity, compared topropofol. Accordingly, the present invention also provides each of theseisomers, their para-fluoro derivatives and pharmaceutically acceptablesalts and pro-drugs thereof, and pharmaceutical compositions thereof,for use as anesthetics.

The (S,S) or (+) and (meso) stereoisomers of formula (I), their saltsand prodrugs thereof may each be prepared following the general methodsdescribed for the preparation of the corresponding (R,R) or (−)stereoisomers. For example, the stereoisomers may be separated from theracemic compound by chiral phase chromatography, for example asdescribed in Example 2 herein. It has been found that the (S,S) or (+)stereoisomer of 2,6-di-sec-butylphenol may advantageously be prepared byreacting a racemic mixture of the corresponding 2,6-di-sec-butylphenolwith an acyl halide (for example an aroyl halide such as benzoylchloride) to afford a mixture of carbonate diastereomers that can beseparated to yield the desired diastereomer of formula (I) afterhydrolysis of the carbonate residue. An example of such a process isdescribed in Example 5a hereinafter.

The (S,S) or (+) and (meso) stereoisomers of formula (I) may exist, beformulated and be administered to patients as described and exemplifiedherein for the (R,R) or (−) stereoisomers. For the (S,S) or (+)stereoisomers, the dosage level for producing general anesthesia may bein the range of from about 1 to about 12 mg/kg. Preferred inductiondoses range from about 1.2 to about 4 mg/kg. Preferred maintenance dosesrange from about 1.5 to about 30 mg/kg/hr. Preferred doses to produce asedative effect range from about 0.5 to about 12 mg/kg/hr. For the(meso) stereoisomers, the dosage level for producing general anesthesiamay be in the range of from about 1 to about 10 mg/kg. Preferredinduction doses range from about 1 to about 3 mg/kg. Preferredmaintenance doses range from about 1 to about 20 mg/kg/hr. Preferreddoses to produce a sedative effect range from about 0.3 to about 8mg/kg/hr.

The ability of a compound of the invention to produce a sedative orhypnotic effect can be determined using standard pharmacological modelswhich are well known to the art. The hemodynamic profile of a compoundof the invention can be determined using standard pharmacological modelswhich are well known to the art.

The invention will now be illustrated by the following non-limitingExamples.

EXAMPLE 1

Isolation of Stereoisomer of a Compound of Formula (I) Via HPLCSeparation of Diasteriomeric Carbamates of 2,6-Di-sec-butylphenol.

Synthesis of R-(+)-1-Phenyl-ethyl)-carbamic acid 2,6-di-sec-butylphenylester (1): A mixture of 2,6-di-sec-butylphenol (2.06 g, 10 mmol), R-(+)1-phenylethylisocyanate (1.47 g, 10 mmol), and 4-(dimethylamino)pyridine(0.06 g, 0.5 mmol) was heated at 100° C. in 10 ml dry pyridineovernight. The reaction mixture was evaporated, and the resultingresidue was treated with ethyl acetate (75 ml) and 1M HCl aq (100 ml).The organic layer was washed twice with 1M HCl aq (2×100 mL), brine (100ml) and dried over anhydrous MgSO₄. Evaporation of the solvent providedcarbamate (1) (3 g, 85%).

Separation of diastereomers of R-(+)-1-Phenyl-ethyl)-carbamic acid2,6-di-sec-butylphenyl ester (1b): HPLC separation was performed on HPLCsilica gel column (250×41.5 mm), sorbent Si-60A 10 mm. Gradient:hexanes-ethyl acetate 0-10% in 72 min; flow rate 50 ml/min; loading 1 gof (1) in 10 ml hexane. The fraction with the desired isomer of thecarbamate (1b) were collected and evaporated (0.18 g, 72%).

Analysis of optical purity by chiral chromatography: Analyses2,6-di-sec-butylphenols were performed on CHIRALCEL OD-H column (4.6×250mm) in isocratic mode, mobile phase—n-hexanes, flow rate 1 ml/min, 20min, detection 270 nm. Samples were dissolved in hexanes. Carbamateswere preliminary hydrolyzed to 2,6-di-sec-butylphenols at 100° C. for1-2 min. in a 1:1 mixture dioxane:1M NaOH aq. 2,6-Di-sec-butylphenolswere extracted with ether. The ether layer was evaporated, and theresidual oil was dissolved in n-hexanes.

Synthesis of (−)-2,6-di-sec-butylphenol (2):R-(+)-1-Phenyl-ethyl)-carbamic acid (+2,6-di-sec-butylphenyl ester (1b)(4.1 g, 11.6 mmol) was dissolved in a 100 ml 1:1 mixture of dioxane: 1MNaOH aq. The reaction mixture was stirred at 70° C. for 15 min.Volatiles were removed at reduced pressure to a volume of ˜50-70 ml. ThepH was adjusted to 3-4 with 1M HCl. The phenol was extracted with ether(3×50 ml), washed with 1 M HCl, brine and dried over anhydrous MgSO₄.Evaporation yielded crude yellow oil (2.4 g, ˜100%). Vacuum distillationwas performed (120-125° C./-5 mm) (2.1 g, 89%). Optical rotation: α²⁰_(D)=−14.11° (c=2, pentane).

EXAMPLE 2

Direct Separation of Stereoisomers of 2,6-di-sec-butylphenol.

Separation of the mixture of stereoisomers of 2,6-di-sec-butylphenol wasachieved by chiral HPLC. 2,6-Di-sec-butylphenol (1 mg/ml in HPLC graden-hexane) was injected onto a chiral HPLC column (Daicel, Inc.,CHIRALCEL OD-H 20×250 mm, 5 um). Separation was achieved using anisocratic gradient using HPLC grade n-hexane as the mobile phase at aflow rate of 10 ml/minute at ambient temperature. Peak detection was at270 mm. 2,6-Di-sec-butylphenol showed three peaks in a 1:2:1 ratiocorresponding to enantiomer 1 (the desired stereoisomer),(meso)-2,6-di-sec-butylphenol, and enantiomer 2. The isolated enantiomer1 (1 mg/ml) was dissolved in HPLC grade n-hexane and injected onto achiral HPLC column (Daicel, Inc., CHIRALCEL OD-H 4.6×250 mm, 5 um), runwith an isocratic gradient using HPLC grade n-hexane as the mobile phaseat a flow rate of 0.7 ml/minute at ambient temperature. Peak detectionwas at 270 mm., and showed a retention time of 17.1 minutes, and apurity of >%99 of the isomer. Optical rotation: α²⁰ _(D)=−11.91°.Following the same analytical procedure as for enantiomer 1, enantiomer2 showed a retention time of 19.6 minutes, and a purity of >%95 of theisomer, and (meso)-2,6-di-sec-butylphenol showed a retention time of18.8 minutes, and a purity of >%96 of the isomer.

EXAMPLE 3 Formulation

The following illustrates a representative dosage form containing acompound of formula (I) for therapeutic use.

Ingredient Batch Weight w/w % Soybean Oil 70 g 11.71 SoybeanPhospholipids 8.4 g 1.41 (Lipid S-75) Compound of formula (I) 3.5 g 0.59Glycerine 15.75 g 2.64 Disodium Edetate 0.035 g 0.01 Sodium Hydroxide(pH adjustment) Subtotal 97.685 Sterile Water For Injection 500 ml 83.66Total 597.685 100

EXAMPLE 4 Formulation

The following illustrates a representative dosage form containing acompound of formula (I) for therapeutic use.

Ingredient Batch Weight w/w % Soybean Oil 70 g 11.66 SoybeanPhospholipids 8.4 g 1.40 (Lipid S-75) Compound of formula (I) 6.0 g 1.00Glycerine 15.75 g 2.62 Disodium Edetate 0.035 g 0.01 Sodium Hydroxide(pH adjustment) Subtotal 100.185 Sterile Water For Injection 500 ml83.31 Total 600.185 100

EXAMPLE 5 Preparation of (R,R)-Di-Sec-Butylphenol Using Chromatographyto Separate Carbamate Diastereoisomers a)(R)-(+)-1-Phenyl-ethyl)-carbamic acid-2,6-di-sec-butylphenyl ester

Di-sec-butylphenol (available from Acros & AK Scientific) (5 grams (g).21.1 millimoles (mmol)) was azeotropically dried on a rotavap (55° C.,48 torr) using 5 milliliters (ml or mL) of toluene and then charged intoa 100-ml three-necked flask equipped with a magnetic stirrer, a refluxcondenser, a thermocouple and a nitrogen (N₂) inlet. Toluene (10 ml) and4-dimethylaminopyridine (0.085 g, 0.7 mmol) were added.(R)-(+)-1-phenylethyl isocyanate (3.5 g, 3.65 ml, 23.63 mmol) wasintroduced last. The resulting clear yellow mixture was heated under N₂at 90° C. using a heating mantle and continued to stir at thistemperature while monitoring the progress of the reaction by highpressure liquid chromatography (HPLC). After the reaction was finished(18-24 hours (h)) as judged by HPLC, the reaction mixture wasconcentrated on a rotavap (50-55° C./45-50 torr) to obtain a semi-solid(˜9.4 g) which was dissolved in hot 2-propanol (18 ml). The solution wasallowed to reach ambient temperature, seeded with pure(R)-(+)-1-Phenyl-ethyl)-carbamic acid-2,6-di-sec-butylphenyl ester, andplaced in a refrigerator (4° C.) for 24-36 h for slow crystallization tooccur. The precipitated yellow solids were filtered cold and dried onthe filter funnel for 1-2 h. The first crop of product weighed 2.8 g(37.5% yield) and was found to be greater than (>) 95 area percent (A %)pure by HPLC analysis. The mother liquor was concentrated on a rotavapto ˜⅔ of the original volume (distilled off 4 ml of 2-propanol), andthen cooled to 0-5° C. for 6-8 h. The second crop of product wasfiltered cold, dried on the filter funnel to give an additional 2.6 g(34.9% yield) of product which was found to be ˜88 A % by HPLC.

b) (R,R,R)-1-phenylethylcarbamic acid-2,6-di-sec-butylphenyl ester

To an Agilent HPLC system fitted with a diode array detector and a 0.46cm ID×25 cm long 10 mm KROMASIL Silica Column was charged 714 mg ofracemic R-(+)-1-phenyl-ethyl)-carbamic acid-2,6-di-sec-butylphenyl esterdissolved in 10 ml of hexane/ethyl acetate (98:2) to give a 71.4 g/lfeed solution. The sample was eluted with hexane/ethyl acetate (98:2) at2 ml/min at 25° C. Fractions containing (R,R,R)-1-phenylethylcarbamicacid-2,6-di-sec-butylphenyl ester were collected and evaporated underreduced pressure at <55° C. At the highest loading, the(R,R,R)-stereoisomer was collected with a chiral purity of 98.7%diastereomeric excess (de) and a total yield of 53%.

c) (R,R)-Di-sec-butylphenol

To a 100-ml three-necked flask equipped with a magnetic stirrer, areflux condenser, a thermocouple and an N₂ inlet, was addedtetrahydrofuran (THF) (9 ml), (R,R,R)-1-phenylethylcarbamicacid-2,6-di-sec-butylphenyl ester (1 g, 2.8 mmol), and 1.0 M sodiumhydroxide (11.4 ml, 11.4 mmol). The resulting clear mixture was heatedunder N₂ at 55-60° C. using a heating mantle and continued to stir atthis temperature while monitoring the progress of the reaction by HPLC.After the reaction was finished (6-8 h) as judged by HPLC, the reactionmixture was cooled to 15° C. and filtered to remove precipitated urea.The filtered cake was washed with cold THF (5 ml). The filtrate and thewash were combined, acidified to pH 2-3 with 3.0 M hydrochloric acid(HCl) (3.5 ml). After stirring for 10 minutes (min), ether (10 ml) wasadded and then resulting mixture was vigorously stirred for 15 min afterwhich layers were separated. The organic layer was washed with 3.0 M HCl(3 ml), brine (5 ml), dried magnesium sulfate (MgSO₄), filtered toremove the drying agent, and then concentrated on a rotavap to give asemi solid yellow residue which was stirred with methyl tertiary butylether (MTBE) (3 ml) for 15 min and then filtered. The filtered cake waswashed with MTBE (2 ml). The filtrate and the wash were combined, andthen concentrated on a rotavap to give the title compound as a yellowoil (0.6 g, 100% crude yield) that was found to be greater than 93 A %pure by HPLC. The NMR (DMSO-d₆) was found to be consistent with thestructure.

EXAMPLE 5a Preparation of (S,S)-di-sec-butylphenol Using Chromatographyto Separate Carbonate Diastereoisomers a) 2,6-di-sec-Butylphenol benzoylester

Di-sec-butylphenol (available from Acros & AK Scientific) is dried on arotavap (55° C., 48 torr) using toluene and then charged into a100-milliliter (ml or mL) three-necked flask equipped with a magneticstirrer, a reflux condenser, a thermocouple and a nitrogen (N₂) inlet.Toluene and 4-dimethylaminopyridine are added followed by benzoylchloride. The resulting mixture is heated under N₂ at 90° C. using aheating mantle and continued to stir at this temperature whilemonitoring the progress of the reaction by high performance liquidchromatography (HPLC). After the reaction is finished as judged by HPLC,the reaction mixture is concentrated on a rotavap (50-55° C./45-50 torr)to obtain a semi-solid.

b) (S,S)-2,6-di-sec-butylphenol benzoyl ester

To an Agilent HPLC system fitted with a diode array detector and a 0.46cm ID×25 cm long 10 mm KROMASIL Silica Column is charged2,6-di-sec-butylphenol benzoyl ester dissolved in hexane/ethyl acetate(98:2) to give a feed solution. The sample is eluted with hexane/ethylacetate (98:2) at 25° C. Fractions containing(S,S)-2,6-di-sec-butylphenol benzoyl ester are collected and evaporatedunder reduced pressure at <55° C. to give a thin oil.

c) (S,S)-Di-sec-butylphenol

To a 100-ml three-necked flask equipped with a magnetic stirrer, areflux condenser, a thermocouple and an N₂ inlet, is addedtetrahydrofuran (THF), (S,S)-2,6-di-sec-butylphenol benzoyl ester, and1.0 M sodium hydroxide. The resulting mixture is heated under N₂ at55-60° C. using a heating mantle and continued to stir at thistemperature while monitoring the progress of the reaction by HPLC. Afterthe reaction is finished as judged by HPLC, the reaction mixture iscooled to 15° C. and filtered to remove precipitated urea. The filteredcake is washed with cold THF. The filtrate and the wash are combined,acidified to pH 2-3 with 3.0 M hydrochloric acid (HCl). After stirringfor 10 min. ether is added and the resulting mixture is vigorouslystirred for 15 min after which layers are separated. The organic layeris washed with 3.0 M HCl, brine, dried magnesium sulfate (MgSO₄),filtered to remove the drying agent, and then concentrated on a rotavapto give a residue which is stirred with methyl tertiary butyl ether(MTBE) for 15 min and then filtered. The filtered cake is washed withMTBE. The filtrate and the wash are combined, and then concentrated on arotavap to give the title compound.

Biological Tests

The pharmacological profile of (R,R)-di-sec-butylphenol was evaluated incomparison with propofol in the tests described in the followingExamples. In these Examples, (R,R)-di-sec-butylphenol is referred to asCompound 1.

EXAMPLE 6 Rat Hippocampal Brain Slice Assay

The abilities of Compound 1 and propofol to potentiate the action ofagonists at the g-aminobutyric acid receptor sub-type A (GABA_(A)receptor) were tested and compared in a rat hippocampal brain sliceelectrophysiology assay.

Compound 1, prepared as described in Example 5, and propofol were eachtested at five concentrations: 0.1, 1, 3, 10 and 30 micromolar (μM).Stock solutions of 100 millimolar (mM) propofol and of 100 mM Compound1, each in DMSO, were diluted into saline to achieve the respectiveconcentrations; 30 μM samples contained 0.03% DMSO; solutions containingup to 0.1% DMSO have no significant effect on the brain slice assay.EC50 and EC20 values were determined using a procedure similar to thatdescribed in Casasola et al. 2002, Epilepsy Research 47, 257, withmodifications as set forth below.

Rat hippocampal slices were prepared as follows: Male Wistar rats(100-125 g) were anesthetized with isoflurane and decapitated, thebrains quickly removed, collected, blocked, and cut using a vibratome(OTS-4000, Electron Microscope Sciences) into 400 micron (μm) transversesections. Slices were transferred to a warmed (33° C.), submergedtissue-recording chamber perfused at 2.5-3 ml/min with modifiedartificial cerebrospinal fluid (120 mM sodium chloride. 3.5 mM,potassium chloride, 2.5 mM calcium chloride, 1.3 mM magnesium chloride,1.25 mM sodium phosphate, 26 mM sodium carbonate, 10 mM glucose,saturated with 95% oxygen, pH 7.4). Hippocampal slices were equilibratedin the recording chamber for at least 1 hour.

Electrophysiology testing was accomplished as follows: A glass rodelectrode (1-2 μM tip diameter) was filled with 3M sodium chloride(NaCl) and placed in the CA1 pyramidal cell layer of hippocampal slices.A 25 μM concentric bipolar stimulating electrode (SNE-100, RhodesMedical Supply) was placed in the stratum radiatum of the CA1 area tostimulate the Schaffer collateral/commissural pathway. Populationresponses of the CA1 pyramidal cells were recorded with an Axoprobe-1A(Axon Instruments, Molecular Devices, Sunnyvale, Calif.). pCLAMP 8.2(Axon Instruments) was used for acquiring the data, and Clampfit (AxonInstruments) was used for analysis. Stimulation consisted of a singlesquare-wave pulse (0.3 millisecond (msec) duration) from the Grass S11Stimulator (Grass Medical Instruments) and was delivered every 20 secthroughout the experimental period. The stimulus intensity was adjustedto evoke a response 80-90% of the maximum. Peak to peak amplitude of thepopulation response from each stimulus was measured as an indicator ofcell excitability.

Compound 1 and propofol, each in the presence of EC20 of muscimol (2 μM)were each sequentially perfused, starting from the lowest to the highestconcentration, in the modified artificial cerebrospinal fluid ofrespective hippocampal slices. The effects of each concentration weremeasured from 4 to 7 min after Compound 1 or propofol application,respectively, at which time changes in the response were found to bestable. Muscimol (10 μM) was applied following the application ofCompound 1 or propofol to verify the sensitivity of the preparation onlyif Compound 1 or propofol did not produce an adequate inhibition of theamplitude of the CA1 population spike (<90% inhibition). GABA_(A)receptor channel antagonist picrotoxin (50 μM) was applied at the end ofthe recording to confirm that the response was mediated by GABA_(A)receptor.

Data were acquired and analyzed using Clampfit and Excel (Microsoft),and reported as mean and individual values. The degree of populationeffect (%) was obtained by measuring the amplitude of the CA 1population spike before (control) and after co-application of muscimol(EC20) and Compound 1 or propofol (the difference was normalized tocontrol and multiplied by 100 to obtain the percent effect.

The data demonstrated that Compound 1 was a potent potentiator of theaction of agonists at the GABA_(A) receptor in the rat hippocampal brainslice, with an EC50 of 2.5 μM. Propofol had an EC50 of 4.8 μM. ThusCompound 1 behaved similarly to propofol in the hippocampal brain sliceassay and fully potentiated the muscimol-mediated response at theGABA_(A) receptor.

EXAMPLE 7 Target Specificity Studies

The abilities of Compound 1 and propofol to interact with a variety ofbiological targets were tested and compared.

Pharmacological profilings of Compound 1, prepared as described inExample 5, and propofol were performed by Cerep, Inc. (Redmond, Wash.,USA) in their “Diversity Profile”, a standard profile of 71 receptors(59 peptide, non-peptide, or nuclear receptors; 7 ion channels; 5 aminetransporters) and 16 enzymes. Compound 1 and propofol were each testedat 10 μM, a therapeutically relevant concentration.

The results indicated that Compound 1 behaved similarly to propofol withrespect to the 71 receptors and 16 enzymes tested. For example, Compound1 and propofol each showed the greatest effect (greater than 30%inhibition of control binding) in the assay measuring picrotoxinin(active compound of picrotoxin) binding at the chloride channel isolatedfrom rat cerebral cortex. This g-aminobutyric acid (GABA) ligand gatedion channel is a central target of action for propofol. Furthermore,Compound 1 and propofol each showed greater than 20% inhibition ofcontrol binding to only one of the 16 enzymes tested: phosphodiesterase2 (PDE2). No significant effects were observed for alpha2, NMDA, PCP,benzodiazepine or opioid receptors.

EXAMPLE 8 Pain on Injection Aqueous Phase Concentration

Injection pain, a common problem of propofol administration, is thoughtto be caused by propofol present in the aqueous phase of the lipidemulsion (see, e.g., Klement W et al, 1991, Br Anaesth 67, 281). Severalstudies have reported a significant decrease in pain on injection whenthe aqueous phase concentration of propofol is reduced compared to theamount of propofol in the aqueous phase of DIPRIVAN (see, e.g. DoenickeA W et al, 1996, Anesth Analg 82, 472; Ueki R et al, 2007, J Anesth 21,325).

The concentration of Compound 1 in the aqueous phase (aqueous phaseconcentration) of a lipid emulsion formulation was determined. Thisaqueous phase concentration was compared to that of propofol formulatedin the same formulation and to that of DIPRIVAN® (AstraZeneca,Wilmington, Del., USA).

A one percent (1%) Compound 1 formulation was formulated in accordancewith Example 4, Compound 1 being prepared as described in Example 5. A1% propofol formulation was formulated in the same manner. DIPRIVAN (1%propofol injectable emulsion) was used as purchased from AstraZeneca.

The aqueous phase concentrations of Compound 1 and propofol weredetermined using the ultrafiltration method described by Teagarden D Lat al., 1988, Pharmaceutical Research 5, 482. Briefly, four 0.4-mlsamples of the 1% Compound 1 formulation, four 0.4-ml samples of the 1%propofol formulation, and two 0.4 samples of DIPRIVAN were placed inUltrafree®-MC microcentrifuge filters (Millipore, Billerica, Mass.) andthe aqueous phases separated from the lipid phases bymicrocentrifugation for 15 min at 5000 rpm. The concentrations ofCompound 1 and propofol in the respective aqueous phases were quantifiedby liquid chromatography tandem mass spectrometry (LC/MS/MS) againststandard curves of Compound 1 and propofol using thymol as an internalreference standard (analyses performed by Alturas Analytics Inc.,Moscow. ID).

The aqueous phase concentration of Compound 1 in the 1% Compound 1formulation was 0.38±0.02 μg/mL. The aqueous phase concentration ofpropofol in the 1% propofol formulation was 6.28±0.41 μg/mL. The aqueousphase concentration of propofol in DIPRIVAN was 4.1 μg/mL.

These results demonstrated a 94% reduction in the aqueous phaseconcentration of Compound 1 compared to that of propofol in identicalformulations, and a 91% reduction in the aqueous phase concentration ofCompound 1 compared to that of propofol in DIPRIVAN.

EXAMPLE 9 Pharmacokinetic Studies

Pharmacokinetic (PK) studies were conducted in domestic pigs to evaluatethe pharmacodynamic effects of Compound 1 and to compare such effects tothose of propofol.

A 1% Compound 1 formulation, prepared as described in Example 5 andformulated in accordance with Example 4, was administered to 6 pigs viaa 20-min intravenous (IV) infusion at 0.380 mg/kg/min (7.6 mg/kg totaldose) and to one pig at 0.456 mg/kg/min (9.12 mg/kg total dose). Plasmaconcentrations of Compound 1 were compared to historical propofol datagenerated per a similar protocol in which a 1% propofol formulation,formulated in the same manner as Compound 1, was administered to 5 pigsvia a 10-min IV infusion at 0.750 mg/kg/min (7.5 mg/kg total dose).

Data from this study indicated that Compound 1 exhibited a similarpharmacokinetic profile to propofol in the pig model. Athree-compartment model best described the Compound 1 and propofol data.Clearance of Compound 1 exceeded estimated hepatic blood flow, similarto propofol. Compound 1 also exhibited a similar metabolic pathway inpigs to that of propofol in humans: glucuronidation in the 1-positionwith the 4-position being subject to hydroxylation followed byglucuronide and sulfate conjugation. A dose-escalation study in dogshowed similar plasma concentrations at washout for Compound 1 andpropofol indicating similar clearance rates in that species as well.

EXAMPLE 10 Anesthetic Effects in Rats

The anesthetic dose response of bolus IV injection of Compound 1,compared to propofol, was studied in rats.

A validated rodent model of general anesthesia (see Hill-Yenning C etal., 1996, Neuropharmacology 35, 1209: Lingamaneni R et al., 2001.Anesthesiology 94, 1050) was used to provide a measure of onset andduration of anesthesia as demonstrated by the Loss of Righting Reflex(LORR) and recovery time (time interval from return of righting reflexuntil the rat was able to grip and climb a steel frame and ambulatenormally). Also measured was minimum dose to achieve LORR and maximumtolerated dose (MTD).

A 1% Compound 1 formulation, prepared as described in Example 5 andformulated in accordance with Example 4, or DIPRIVAN was administered bybolus IV injection at 2.5 ml/min to 6 male Sprague-Dawley rats (200-300g) per dose group for the amount of time required to administer thedoses described below. The relative potency was assessed by determiningthe dose required to cause 50% of the rats to lose righting reflex(HD50) and the dose required to produce 7 minutes of anesthesia (HD7min). The ranges of doses studied were 1.9, 2.3, 3.0, 7.0, 13.7, 14.0and 15.2 mg/kg for Compound 1 and 3.5, 4.0, 7.0 and 14.0 mg/kg forDIPRIVAN.

Results indicated that bolus IV administration of Compound 1 produceddose-dependent duration of anesthesia in rats. Onsets of LORR were lessthan 15 sec when the respective drugs were administered at a dose of atleast 3.0 mg/kg for Compound 1 and at a dose of at least 7.0 mg/kg forpropofol. Compound 1 produced no LORR at 1.9 mg/kg but did produce LORRat all other doses tested. Propofol produced no LORR in 4 of 6 ratstested at 3.5 mg/kg, but did produce LORR at all other doses tested.Table 1 compares the HD50, HD7 min, MTD, and therapeutic index (TI;defined herein as the ratio of MTD to HD7 min) results for Compound 1and propofol. One rat died when administered 14 mg/kg DIPRIVAN. Two ratsdied when administered 15.2 mg/kg of Compound 1. Recovery time showedlittle relationship to dose except for high doses of Compound 1, whichalso produced prolonged LORR.

TABLE 1 Comparison of HD50, HD7 min, MTD and TI results for Compound 1and propofol administered by bolus IV to rats. Propofol Compound 1 HD50 3.8 mg/kg 2.1 mg/kg HD7 min  7.0 mg/kg 2.3 mg/kg MTD <14 mg/kg  14mg/kg TI <2 6.1

In summary, Compound 1 showed potency at lower doses than propofol andalso showed a higher MTD and improved TI compared to propofol.

(S,S)-2,6-di-sec-butylphenol, prepared in accordance with Example 2, wasalso evaluated in this test at doses of 2, 3, 4, 5, 6, 28, 35, 42, 49and 56 mg/kg. Table 1a indicates HD50, HD7 min, MTD, and TI results forthis compound. One of six rats died when administered 49 mg/kg of(S,S)-2,6-di-sec-butylphenol.

TABLE 1a HD50, HD7 min, MTD and TI results for(S,S)-2,6-di-sec-butylphenol administered by bolus IV to rats. (S, S)HD50   4 mg/kg HD7 min 5.2 mg/kg MTD  42 mg/kg TI 8.1

In a separate study, rats were administered 7 mg/kg of 1% Compound 1 incremaphor or propofol, (S,S)-2-6-di-sec-butylphenol or(meso)-2-6-di-sec-butylphenol (prepared in accordance with Example 2) atthe same doses and formulations. The results are shown in Table 1b. Oneof 6 rats administered 21 mg/kg of 1% (meso)-2-6-di-sec-butylphenolformulated in cremaphor died; however, the remaining 5 rats exhibited 34min of anesthesia.

TABLE 1b Comparison of duration of anesthesia (sleep time) for 7 mg/kgadministrations of Compound 1, propofol, (S,S)-2-6-di-sec-butylphenoland (meso)-2-6-di-sec-butylphenol by bolus IV to rats. Sleep TimePropofol  7.1 min Compound 1   23 min (S,S)  6.3 min (meso) 12.7 min

In summary, the potency of (S,S)-2-6-di-sec-butylphenol was similar topropofol. The potency of (meso)-2-6-di-sec-butylphenol was improvedcompared to propofol. Both stereoisomers exhibited improved MTD andtherapeutic indices compared to propofol.

EXAMPLE 11 Anesthetic and Hemodynamic Effects in Beagle Dogs

A dose-escalation study was conducted in dogs to demonstrate theanesthetic and hemodynamic effects of bolus IV administration ofCompound 1 compared to propofol.

The endpoints for this study were dose relationship for induction,duration, depth and quality of anesthesia and hemodynamic effects ofbolus IV administration of Compound 1 or propofol. A 1% Compound 1formulation, prepared as described in Example 5 and formulated inaccordance with Example 4, and a 1% propofol formulation formulated inthe same manner were used.

Electroencephalographic (EEG) measurement of depth of anesthesia wasmeasured with Bispectral Index (BIS), which is one of several systemsused to measure the effects of anesthetic drugs on the brain and totrack changes in the level of sedation or anesthesia. BIS is amathematical algorithm that analyzes data from the EEG, and the outputis a single number from 100 (fully conscious,) to 0 (isoelectric EEG).Other assessments included sedation scores, clinical observations, bloodpressure, electrocardiogram (ECG), and oxygen saturation.

Beagle dogs (male, 2-4 years old, 8-10 kg) were implanted with vascularaccess ports. At the time of implant surgery, the dogs' heads wereshaved, marked for EEG electrode placement and injected with BOTOX®(Allergan, Inc. Irvine, Calif.; botulinum toxin type A purifiedneurotoxin complex): 40 units total per dog in 5 intramuscular (IM)injections across the brow were administered. The injections wereintended to suppress muscular movement and electromyographic (EMG)interference with the BIS signal.

The study was a crossover design. Each dog received 2 to 4 escalatingbolus IV doses (injected over 60 seconds) of Compound 1 or propofolseparated by at least 30 min (or until the dog was awake) until the MTDwas achieved. The MTD was defined as the dose that reduced mean arterialblood pressure (MAP) by 50% or to less than 50 millimeters of mercury(mmHg or mm Hg). All animals received supplemental oxygen and, ifneeded, ventilatory support after 4 min of apnea.

Depth of anesthesia was determined by assessing the presence or absenceof lash reflex, response to glabellar tap or auditory stimulus, toepinch, and breathing. Presence of each sign was scored as 1 and absenceof each as 0. This allowed calculation of a Cumulative Sedation Score atmultiple time points over the 30 min between doses (5=awake,0=apneic/deep anesthesia). The quality of anesthesia was assessed bynoting the smoothness of induction, qualitative assessment of muscletone, and presence of involuntary motion. Episodes of involuntarymovements (e.g. during emergence) were scored as present or absentthroughout the observation period for each dose. BIS and hemodynamiceffects were analyzed with 2-way ANOVA followed by t-test withBonferroni correction for multiple comparisons of the effect of time anddose.

A. Anesthetic Effects

The abilities of Compound 1 and propofol administered by bolus IV toeffect dose-related anesthesia in unpremedicated spontaneously breathingbeagles (3.3-30 mg/kg/dose; 1-10 dogs per dose) are demonstrated inTable 2. Two of 3 dogs administered 15 mg/kg of propofol reached the MTDat 15 mg/kg. Therefore, only 1 dog was given the 30 mg/kg propofol dose.

TABLE 2 Dose-related duration of anesthesia (sleep time) for Compound 1and propofol after bolus IV administration to dogs. Dose PropofolCompound 1  5 mg/kg 13 min  24 min 10 mg/kg 28 min  43 min 15 mg/kg 43min  77 min 30 mg/kg 69 min 105 min

The data also indicated that anesthesia was induced within 1 min at alldoses for Compound 1 and propofol. Duration of anesthesia, measured bysleep time, was longer with Compound 1 than propofol at all doses.Cumulative sedation scores demonstrated approximately equipotentanesthetic depth for both propofol and Compound 1 above 5 mg/kg. Therewas no significant difference between BIS values for dogs administeredCompound 1 at 10 mg/kg or propofol at 10 mg/kg or 15 mg/kg. Compound 1produced a greater effect on BIS at doses of at least 15 mg/kg but thesedoses are very high, and potentially not clinically relevant. Thequality of anesthesia (smoothness of induction, qualitative assessmentof muscle tone, presence of involuntary motion) of Compound 1 wassimilar to propofol.

(S,S)-2,6-di-sec-butylphenol and (meso) 2,6-di-sec-butylphenol, producedin accordance with Example 2, were also evaluated in this test. Table 2ashows the dose-related duration of anesthesia (sleep time) for thesecompounds.

TABLE 2a Dose-related duration of anesthesia (sleep time) for(S,S)-2,6-di-sec-butylphenol and (meso) 2,6-di-sec-butylphenol afterbolus IV administration to dogs. Dose (S,S) (meso)  5 mg/kg  8 min 25min 10 mg/kg 24 min 36 min 15 mg/kg 50 min 55 min 30 mg/kg 50 min 58 min

The data also indicated that anesthesia was induced within 1 min at alldoses for (S,S)-2,6-di-sec-butylphenol and (meso)2,6-di-sec-butylphenol. Duration of anesthesia, measured by sleep time,was similar to propofol for (S,S)-2,6-di-sec-butylphenol and longer for(meso) 2,6-di-sec-butylphenol. The quality of anesthesia of(S,S)-2,6-di-sec-butylphenol was similar to propofol but was inferiorfor (meso) 2,6-di-sec-butylphenol.

B. Hemodynamic Effects: Blood Pressure

Hemodynamic data, such as mean arterial pressure (MAP), were recorded atbaseline, 1, 2, 4, 8, 15, 20 and 30 min. Compound 1 was administered at5, 10, 15 and 30 mg/kg to 3, 6, 6 and 3 dogs respectively. Propofol wasadministered at the same doses to 3, 5, 5, and 1 dogs, respectively.Only 1 dog received 30 mg/kg propofol because the MTD criteria werereached with 15 mg/kg in two animals. Data were analyzed with a 2-wayANOVA followed by t-test with Bonferroni correction for multiplecomparisons.

A comparison of the data indicated that propofol produced asignificantly greater effect on MAP than does Compound 1. Table 3provides an example in which mean arterial pressure percent (MAP %)changes from baseline 4 min after bolus IV administration of 10, 15 or30 mg/kg of Compound 1 are compared to MAP % changes effected by thesame doses of propofol.

TABLE 3 Dose-related mean arterial pressures changes measured as MAP %change from baseline 4 min after bolus IV administration of Compound 1or propofol to dogs. Dose Propofol Compound 1 10 mg/kg −22% +11% 15mg/kg −32% −25% 30 mg/kg  −66%* −41% *Only 1 dog was tested at 30 mg/kgpropofol in view of 2 dogs having reached the MTD criteria at 15 mg/kgpropofol.

(S,S)-2,6-Di-sec-butylphenol and (meso)-2,6-di-sec-butylphenol, producedin accordance with Example 2, were also evaluated in this test. Acomparison of the data indicated that propofol produced a significantlygreater effect on MAP than do (S,S)-2,6-Di-sec-butylphenol or(meso)-2,6-di-sec-butylphenol. Table 3a provides an example, comparingMAP % changes from baseline at 4 min.

TABLE 3a Dose-related mean arterial pressures changes measured as MAP %change from baseline 4 min after bolus IV administration of(S,S)-2,6-Di-sec-butylphenol and (meso)-2,6-di- sec-butylphenol to dogs.Dose (S,S) (Meso) 10 mg/kg +7%  +5% 15 mg/kg +5% +15% 30 mg/kg   0% −16%

EXAMPLE 12 Anesthetic and Hemodynamic Effects in Mongrel Dogs

This study compared the effect of total intravenous anesthesia inchronically instrumented mongrel dogs administered Compound 1 orpropofol. Assessments included hemodynamic performance parameters suchas blood pressure, heart rate, and cardiac output as well as clinicalchemistry parameters and EEG analysis.

A 1% Compound 1 formulation, prepared as described in Example 5 andformulated in accordance with Example 4, and DIPRIVAN (1% propofolinjectable emulsion) were compared in adult (at least 9 months old;approximately 20-40 kg) mongrel dogs.

General anesthesia was induced in the dogs by IV administration of 7mg/kg DIPRIVAN, and the dogs were tracheally intubated and mechanicallyventilated. General anesthesia was maintained using 2.2% end-tidalsevoflurane in oxygen. A thoracotomy was performed at the fifth leftintercostal space, and heparin-filled catheters were placed in theproximal descending thoracic aorta (P50 pressure transducer Gould,Oxnard, Calif.), and in the right and left atria to provide IV access.An ultrasonic transit-time flow probe (T108, Transonic Systems, Ithaca,N.Y.) was placed around the ascending thoracic aorta. A 20 kHz Dopplerflow probe (Model HDP-20-3.5, Triton Surgical Technologies, San Diego,Calif.) was placed around the left anterior descending coronary artery.Six MHz sonomicrometer crystals (Hartley, Houston, Tex.) were implantedin the subendocardium. A high fidelity micromanometer (P7, KonigsbergInstruments, Pasadena. CA) was inserted into the left ventricle. Ahydraulic vascular occluder (In Vivo Metric Systems, Healdsburg, Calif.)was positioned around the thoracic inferior vena cava. Instrumentationwas exteriorized, the chest wall was closed in layers, and thepneumothorax was evacuated. The dogs recovered a minimum of 7 daysbefore experimentation and were acclimated to standing in a sling duringthe recovery period.

The dogs were fasted overnight. Conscious dogs were placed in a sling,and needle electrodes were inserted to record Lead II ECGs. Scalpelectrodes were positioned to record EEGs (MP 150, Biopac Systems,Goleta, Calif.) in 3 bipolar recording configurations that sampledfrontal, temporal, parietal, and occipital regions. The dogs thenreceived a 500 ml IV bolus of normal saline, following which an IVinfusion of normal saline was established at a rate of 3 ml/kg/hr(60-120 ml/hr per dog) for the duration of the experiment. The dogs wereallowed to stabilize for 30 minutes. EEG was recorded continuouslyduring the experiment. Arterial blood gas and chemistry measuresincluded pH, pO₂, sO₂, pCO₂, tCO₂, carbonate, potassium, sodium, andbase excess, and were measured immediately following blood draws using ablood gas and chemistry analyzer (ABL-505, Radiometer, Copenhagen).Blood clinical chemistry measurements included albumin, albumin/globulinratio, alkaline phosphatase, ALT (SGPT), AST (SGOT), bicarbonate, directbilirubin, BUN. BUN/creatinine ratio, calcium, chloride, cholesterol,CK, creatinine, globulin, glucose, phosphorus, potassium, sodium,sodium/potassium ratio, and total protein. Following stabilization,baseline measurements of EEG, hemodynamics, ECG, and blood gases wererecorded. Blood samples were drawn for PK and clinical chemistry, andpressure volume loops were generated and data recorded.

Immediately following baseline measurements, the dogs received a 4 mg/kg(1 dog) or 5 mg/kg (6 dogs) IV bolus dose of Compound 1 or a 7 mg/kg IVbolus dose of propofol (7 dogs) over 1 minute to induce generalanesthesia. Following induction, the dogs were tracheally intubated, andmechanically ventilated using 50% oxygen in nitrogen throughout thesubsequent drug infusion and recovery periods. Beginning 4 minutes afterthe end of the bolus dose, the dogs that received the Compound 1 boluswere administered a series of four 15-minute IV infusions at rates of0.25, 0.5, 1.0 and 2.0 mg/kg/min of Compound 1 in a stepwise crossoverfashion; the same protocol was used for dogs receiving the propofolbolus except that propofol was infused at the indicated rates and times.MAP was monitored continuously, and dosing was discontinued immediatelyif MAP decreased below 50 mmHg at any time or if the heart rateincreased over 200 beats per minute. Dosing was halted in one dog at theend of the 1.0 mg/kg/min Compound 1 infusion period and in two othersduring the 2.0 mg/kg/min Compound 1 infusion period. At the end of each15-minute infusion, measurements of EEG, hemodynamics, ECG, and bloodgases were recorded, blood samples were drawn for PK, and pressurevolume loops were generated and data recorded. Following dosing, thedogs were allowed to recover. Ventilation was discontinued, and thetrachea extubated, when subjective interpretation of clinicalobservations indicated sufficient recovery from general anesthesia. Timeof tracheal extubation was noted. At 30 minutes after the end of thefinal infusion, measurements of EEG, hemodynamics, ECG, and blood gaseswere recorded, blood samples were drawn for PK, and pressure volumeloops were generated and data recorded. Concentrations of Compound 1 andpropofol in dog plasma were determined, and concentrations of 5metabolites (1 oxidative, 3 glucuronide-conjugated, and 1sulfate-conjugated) were estimated, using liquid chromatography (LC) andtandem mass spectrometry (MS/MS) (performed at Alturas Analytics).

Results indicated that arterial blood gas and clinical chemistry datawere stable. EEG analysis showed dose-related sedative-hypnotic effectand no evidence of seizure or pre-seizure activity. All dogs recoveredfrom general anesthesia at a similar rate regardless of whether they hadbeen administered Compound 1 or propofol. Compound 1 and glucuronidemetabolites in both the 1-position and the 4-position were detected inthe plasma. Plasma concentrations were consistent with the drugadministration regimen.

In this model, at therapeutically relevant doses, EEG results showed agreater anesthetic potency effect for Compound 1 compared to propofol.There were no statistically significant differences between MAP andheart rate results for Compound 1 and propofol. Cardiac output inpropofol-treated dogs was significantly reduced from baseline; incontrast, Compound 1-treated dogs exhibited no statistically significantreduction in cardiac output.

EXAMPLE 13 Anesthetic and Hemodynamic Effects in Pigs

Anesthetic and hemodynamic effects of Compound 1 and propofol werecompared in anesthetized ventilated pigs infused IV with a 1% Compound 1formulation, prepared as described in Example 5 and formulated inaccordance with Example 4, or DIPRIVAN (1% propofol injectableemulsion). Assessments included EEG measurements of depth of anesthesiausing BIS, pharmacokinetics, blood pressure, ECG, heart rate, cardiacoutput, body temperature, and oxygen saturation.

Experiments were performed on commercial farm-bred swine of either sex(mean weight 33.6 kg). Anesthesia was induced with isoflurane.Intravascular access was obtained from an ear vein. Each pig wasintubated and mechanically ventilated. Tissue oxygenation was monitoredusing continuous pulse oximetry placed on the tongue. Ventilation wasmonitored using an inspired/expired gas analyzer that measured oxygen,carbon dioxide, and potent inhalation agent concentrations. Ventilatorsettings were adjusted as needed to maintain steady state.

A continuous level of anesthesia was achieved with isoflurane and aninfusion of pancuronium (10 mg/hr). ECG was monitored throughout thestudy. Arterial blood pressure was monitored through the cannulated leftfemoral artery. MAP, systolic and diastolic arterial pressures and heartrate were collected every 5 seconds. An internal jugular vein wascannulated with a pulmonary artery catheter for thermodilution estimatesof cardiac output and blood temperature. Body temperature was maintainedat 37° C. Instrumentation for EEG monitoring was accomplished using anadhesive electrode array over the fronto-occipital regions (AspectMedical. Norwood, Mass., USA).

The experimental design included a 30 min stabilization period, followedby IV infusion of Compound 1 (0.384 mg/kg/min×20 min) or propofol (0.750mg/kg/min×10 min. The respective infusion was followed by a 180 minwashout period. Hemodynamic measurements and blood samples forpharmacokinetic analysis were taken at pre-infusion, every 2 min duringinfusion of Compound 1 or propofol and at frequent intervals during thewashout period. The infusion times and rates for Compound 1 and propofolwere previously determined to produce a maximum reduction of BIS (<10)during the infusion period. Arterial blood samples for determining pH,pO2, pCO2, glucose, potassium, and lactate were measured at baselinebefore Compound 1 or propofol infusion, during infusion, and hourlyafter infusion.

Metabolic and hemodynamic parameters for each group were compared atmultiple time points using an unpaired two-tailed Student t test. Toaccount for multiple comparisons and maintain the probability of a typeI error below 0.05, P values less than 0.025 were consideredsignificant.

A. Anesthetic Effects

Compound 1 and propofol produced maximal suppression of BIS (<10) withIV infusions of 14.7±3.8 min of 384 μg Compound 1 per kg per min and9.4±1.9 min of 750 μg propofol per kg per min, respectively. The effecton EEG was reversible and returned to baseline within 60 min. The areaunder the curve (AUC) of Compound 1 required to reach maximumpharmacodynamic effect (Emax) was significantly smaller than that forpropofol (51.5±15.5 versus 108.7±24.3 μg-min/mL, respectively). Inconclusion, the data indicated that Compound 1 was more potent thanpropofol.

B. Hemodynamic Effects

Mean arterial pressure and heart rate were measured at intervalsthroughout IV infusion and washout with Compound 1 (0.384 mg/kg/min, 5pigs) and propofol (0.750 mg/kg/min. 6 pigs). Results are shown in FIGS.1 and 2 respectively. FIG. 3 compares cardiac output produced byCompound 1 compared to propofol. Arterial blood gas samples from pigsinfused with Compound 1 were taken and analyzed for blood gas and serumchemistry values; mean values are reported in Table 4.

TABLE 4 Arterial blood gas and serum chemistry mean values. Min pH pC02pO2 ABEc Potassium Glucose Lactate 0 7.4861 38.8 390 5.6 3.80 99.6 1.434 7.5027 37.2 410 5.8 3.71 102.9 1.24 20 7.5066 36.8 419 5.7 3.84 102.01.20 80 7.4943 37.5 402 5.4 4.00 99.7 1.01 140 7.4803 37.2 399 4.1 4.10100.7 0.95 200 7.4641 37.6 356 3.2 4.06 102.4 0.96 ABEc refers to acidbase excess, corrected.

Baseline MAP and HR values were not different between Compound 1 andpropofol. Both compounds reduced MAP, but propofol produced asignificantly larger decrease in MAP (66±4) than did Compound 1 (106±3)(p<0.001). The lowest HR measured for propofol (88±6 bpm) wassignificantly lower than the lowest FIR measured for Compound 1 (129±6bpm) (p<0.5). Both MAP and FIR returned to baseline afterdiscontinuation of infusions of Compound 1 or propofol. There was nosignificant difference in the reduction of cardiac output produced byCompound 1 compared to propofol.

Table 4 indicates that all arterial blood gas and serum chemistry valueswere within normal limits: Compound 1 did not produce any significantmetabolic alterations such as metabolic acidosis or increased lactate.

EXAMPLE 14 Anti-Emetic Activity

Compound 1 was tested for its anti-emetic potential in ferrets andcompared to that of propofol.

Male descented ferrets weighing 1.0-1.5 kg with vascular access ports inthe jugular vein were housed on a 12/12-hour light/dark cycle undercontrolled temperature, with food and water provided ad libitum. On eachstudy day, food was presented to ferrets one hour prior to dosing.Immediately prior to dosing, food and water were removed. A 1% Compound1 formulation, prepared as described in Example 5 and formulated inaccordance with Example 4, or DIPRIVAN was administered by IV infusionto the ferrets; see Wynn R L et al, 1993, Eur J Pharmacol 241, 42 reDIPRIVAN administration in ferrets. After administration of Compound 1or DIPRIVAN, animals were placed in clean, transparent cages (with lids)and left unrestrained for a 45-min observation period by an observerblinded to the specific treatment administered.

Emesis in ferrets is characterized by rhythmic abdominal contractionsthat are associated either with the oral expulsion of solid or liquidmaterial from the gastrointestinal tract (i.e., vomiting) or withmovements that do not include passage of material (i.e., retching).Episodes of retching and/or vomiting were considered separate episodeswhen the interval between retches and/or vomits exceeded 5 sec.

Pro-emetic activity of Compound 1 or propofol was studied in 6 ferretsper drug as follows: Ferrets were anesthetized by isoflurane inhalation.Compound 1 or propofol was administered by an IV infusion for 15 min at1 mg/kg/min. After termination of the infusion, the ferrets wereobserved continuously for 45 min, and the number of vomits and retcheswere counted.

Anti-emetic activity of Compound 1 or propofol was studied in 6 ferretsper drug as follows: Ferrets were anesthetized with isoflurane,administered Compound 1 or propofol by a 15 min IV infusion at 1mg/kg/min. After termination of the infusion, 0.5 mg/kg morphine sulfatewas administered subcutaneously and the ferrets were monitored for 45min as described above. Six additional ferrets were administeredsubcutaneously 0.5 mg/kg morphine sulfate only.

Morphine sulfate (0.5 mg/kg) alone was pro-emetic in ferrets, yielding15 episodes of vomiting and 157 retches. Compound 1 did not produce anyepisodes of vomiting or retching when administered alone or in thepresence of morphine. Ferrets that received propofol and morphinesulfate exhibited 3 vomits and 47 retches. Therefore, Compound 1 andpropofol both reduced the incidence of vomiting and retching in thepresence of morphine.

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

1. A (+)-stereoisomer of formula (I):

wherein X is H or F; or a salt or prodrug thereof.
 2. A compound ofclaim 1, wherein X is H.
 3. A compound of claim 1, which is a(+)-stereoisomer of formula (I) or a pharmaceutically acceptable salt orprodrug thereof.
 4. A compound of claim 3, wherein X is H.
 5. A compoundof claim 3, which is a (+)-stereoisomer of formula (I) or apharmaceutically acceptable salt thereof.
 6. A compound of claim 5,wherein X is H.
 7. A pharmaceutical composition comprising a compound offormula (I):

wherein the compound is a (+)-stereoisomer of formula (I) and wherein Xis H or F; or a pharmaceutically acceptable salt or prodrug thereof anda pharmaceutically acceptable carrier.
 8. The pharmaceutical compositionof claim 7, wherein X is H.
 9. The pharmaceutical composition of claim7, which is formulated for intravenous administration.
 10. Thepharmaceutical composition of claim 9, wherein X is H.
 11. Thepharmaceutical composition of claim 9, which is formulated as a lipidemulsion.
 12. The pharmaceutical composition of claim 11, wherein X isH.
 13. A pharmaceutical composition of claim 7, wherein the compound isa (+)-stereoisomer of formula (I) or a pharmaceutically acceptable saltthereof.
 14. The pharmaceutical composition of claim 13, wherein X is H.15. The pharmaceutical composition of claim 13, which is formulated forintravenous administration.
 16. The pharmaceutical composition of claim15, wherein X is H.
 17. The pharmaceutical composition of claim 15,which is formulated as a lipid emulsion.
 18. The pharmaceuticalcomposition of claim 17, wherein X is H.
 19. A method for inducing ormaintaining general anesthesia in an animal comprising administering tothe animal an effective amount of a (+)-stereoisomer of formula (I):

wherein X is H or F; or a pharmaceutically acceptable salt or prodrugthereof.
 20. A method of claim 19, wherein X is H.
 21. A method of claim19, wherein the compound is a (+)-stereoisomer of formula (I) or apharmaceutically acceptable salt thereof.
 22. The method of claim 21,wherein X is H.
 23. A method for promoting sedation in an animalcomprising administering to the animal an effective amount of a(+)-stereoisomer of formula (I):

wherein X is H or F; or a pharmaceutically acceptable salt or prodrugthereof.
 24. A method of claim 23, wherein X is H.
 25. A method of claim23, wherein the compound is a (+)-stereoisomer of formula (I) or apharmaceutically acceptable salt thereof.
 26. The method of claim 25,wherein X is H.
 27. A process for preparing a (+)-stereoisomer offormula (I):

wherein X is H or F; or a salt or prodrug thereof, which comprisesseparating a diastereomeric mixture of 2,6,-di-sec-butylphenol by chiralphase chromatography to obtain the (+) -stereoisomer of formula (I),followed if required by forming the salt or prodrug thereof.
 28. Theprocess of claim 27, wherein the salt is a pharmaceutically acceptablesalt.
 29. The process of claim 27, wherein X is H.
 30. The process ofclaim 27, wherein the process comprises isolating the free phenol orforming the pharmaceutically acceptable salt thereof.
 31. The process ofclaim 30, wherein X is H.